Phosphatidylinositol 3-kinases (PI 3-kinases), a family of enzymes which catalyse the phosphorylation of the 3′-OH of the inositol ring, play a central role in regulating a wide range of cellular processes including metabolism, survival, motility and cell activation (Vanhaesebroeck, B. et al., Annu. Rev. Biochem. 2001, 70, 535). These lipid kinases are divided into 3 major classes, I, II & Ill, according to their structure and in vitro substrate specificity (VVymann, M. et al.; Biochem. Biophys. Acta, 1998, 1436, 127). The most widely understood class I family is further subdivided into subclasses IA and IB. Class IA PI 3-kinases consist of an 85 kDa regulatory/adapter protein and three 110 kDa catalytic subunits (p110α, p110β and p110δ) which are activated in the tyrosine kinase system whilst class IB consists of a single p110γ isoform (PI 3-kinase gamma isoform) which is activated by G protein-coupled receptors. The three members of class II PI 3-kinases (C2α, C2β and C2γ) and single member of class III PI 3 kinases (Vps34) are less well understood. In addition there are also four PI 4-kinases and several PI 3-kinase related protein kinases (termed PIKK's or class IV) including DNA-PK, mTOR, ATM and ATR, all of which have a similar catalytic domain (Abraham R. T. et al.; DNA repair 2004, 3(8-9), 883).
A key role for PI 3-kinase gamma isoform in processes such as leukocyte activation, leukocyte chemotaxis and mast cell degranulation has been shown, thereby generating interest in this target for the treatment of autoimmune and inflammatory disorders (Ghigo et al., Bioessays, 2010, 32, p 185-196; Reif et al., J. Immunol., 2004, 173, p 2236-2240; Laffargue et al., Immunity, 2002, 16, p 441-451; Rommel et al, Nature Rev. Immunology, 2007, 7, p 191; Cushing et al J. Med. Chem., 2012, 55, p 8559; Bergamini et al, Nature Chem. Biol., 2012, 8, p 576). Specifically, numerous publications suggest the potential utility of PI3 Kinase gamma isoform inhibitors for the treatment of asthma (e.g. Thomas et al, Immunology, 2008, 126, p 413; Jiang et al, J. Pharm. Exp. Ther., 2012, 342, p 305; Takeda et al, Int. Arch. Allergy Immunol. 2010, 152 (suppl 1), p 90-95). There are also reports linking inhibition of the PI 3-kinase gamma isoform as having potential therapeutic value in numerous other indications such as cancer (Beagle and Fruman, Cancer Cell, 2011, 19, p 693; Schmid et al, Cancer Cell, 2011, 19, p 715; Xie et al, Biochem. Pharm., 2013, 85, p 1454; Subramaniam et al, Cancer Cell, 2012, 21, p 459), diabetes (Kobayashi et al, Proc. Nat. Acad. Sci, 2011, 108, p 5753; Azzi et al, Diabetes, 2012, 61, p 1509), cardiovascular disease (Fougerat et al, Clin. Sci., 2009, 116, p 791; Fougerat et al, Circulation, 2008, 117, p 1310; Chang et al, Proc. Nat. Acad. Sci., 2007, 104, p 8077; Fougerat et al, Br. J. Pharm., 2012, 166, p 1643), obesity (Becattini et al, Proc. Nat. Acad. Sci., 2011, 108, pE854), Alzheimer's disease (Passos et al, Brain, Behaviour and Immunity, 2010, 24, 493) and pancreatitis (Lupia et al, Am. J. Path, 2004, 165, p 2003). A recent review of PI 3-Kinase isoforms as drug targets is given in Blajecka et al, Current Drug Targets, 2011, 12, p 1056-1081.
WO2009/115517 (Novartis) describes amino pyrazine and pyridine derivatives as PI 3-kinase inhibitors.
WO2009/013348 (Novartis) describes amino pyrimidine derivatives as PI 3-kinase inhibitors.
WO2003/093297 (Exelixis) describes protein kinase modulators and methods of use of such modulators.
Leahy et al., J. Med. Chem., 2012, 55 (11), pp 5467-5482, describe PI 3-kinase gamma isoform inhibitors.
Hence, there is a need for potent, selective inhibitors of PI 3-kinase gamma isoform.